This proposal is designed to develop and test several general and efficient approaches for the enantioselective total synthesis of a wide variety of useful biologically active natural products that have been isolated from marine sources. The target molecules are: pseudopterosin A, an extremely potent antiinflammatory and analgesic agent; the didemnenones, which have shown antibacterial, antifungal, and strong cytotoxic properties; acalycixeniolide A and B, which are cell division inhibitors; and finally, reiswigin A and B, which have exhibited very strong in vitro antiviral activity against a variety of viruses. The key step in the synthesis of each of these molecules generally involves a cyclization (in one case, a 1,4-addition) of a precursor in which a distal and ultimately removable chiral center causes the desired enantiomer of the key intermediate to be formed. In all cases, the syntheses are designed so as to be relatively short (12 steps to didemnenone D, 16 steps for acalycixeniolide A and B) and general enough so that many other structurally related systems could be formed quite easily. At the end of each synthetic scheme, we describe the various analogues of the natural products that we will prepare and have tested. The principles developed in these syntheses - e.g., intramolecular benzyne diene cycloaddition in which a benzylic chiral center determines the relative stereochemistry, enantioselective 1,4-addition of a cuprate to an unsaturated system having an adjacent homochiral ketal, enantiocontrol by an allylic (thiophenyl) methyl moiety in Lewis acid-catalyzed intramolecular Diels-Alder reaction of a tetradecatetraene, stereoselective polyolefinic cyclization with a chiral epoxy alcohol as initiator and stereospecific Lewis acid-promoted epoxy alcohol pinacol-type rearrangement to give hydrazulene derivatives - would be applicable and of great value to organic synthesis in general. Because of the medicinal importance of the targets, the efficiency of bond construction in the syntheses, and the high intrinsic value of the new methods themselves, the likelihood of an important contribution to health-related science is quite high.